Allogenicity of Human Cardiac Stem/Progenitor Cells Orchestrated by Programmed Death Ligand 1

Rationale: Transplantation of allogeneic cardiac stem/progenitor cells (CPC) in experimental myocardial infarction promoted cardiac regeneration and improved heart function. Although this has enhanced prospects of using allogeneic CPC for cardiac repair, the mechanisms regulating the behavior of these allogeneic cells, which are central to clinical applications, remain poorly understood. Objective: T cells orchestrate the allogeneic adaptive immune response. Therefore, to provide insight into the mechanisms regulating the immunologic behavior of human CPC (hCPC), we investigated the allogeneic T-cell response elicited by cryopreserved c-kit-selected hCPC. Methods and Results: By using an experimental model of allogeneic stimulation, we demonstrate that, whether under inflammatory conditions or not, hCPC do not trigger conventional allogeneic Th1 or Th2 type responses but instead induce proliferation and selective expansion of suppressive CD25(high)CD127(low)human leukocyte antigen-DR(+)FoxP3(high) effector regulatory T cells. The regulatory T-cell proliferation and amplification were dependent on the interaction with the B7 family member programmed death ligand 1 (PD-L1), which is substantially expressed on hCPC and increased under inflammatory conditions. Thus, hCPC in allogeneic settings acquire the capacity to downregulate an ongoing immune response, which was dependent on PD-L1. Conclusions: Collectively, these data reveal that hCPC in allogeneic settings have a tolerogenic immune behavior, promoting a contact PD-L1-dependent regulatory response and a PD-L1-dependent allogeneic-driven immunomodulation. Our study attributes an important role for PD-L1 in the immune behavior of allogeneic hCPC and raises the possibility of using PD-L1 expression as a marker to identify and select low-risk high-benefit allogeneic cardiac repair cells. (Circ Res. 2013;112:451-464.)